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Bo Liu,* Yao Zhang,* Zheng Yuan, Qiang Zhang Department of Orthopaedics, Beijing Ditan Hospital, Capital Medical University, National Center for Infectious Diseases, Beijing, 100015, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiang Zhang, Department of Orthopaedics, Beijing Ditan Hospital, Capital Medical University, National Centre for Medical Infectious Diseases, No. 8 Jingshun Eest Road, Beijing, 100015, People’s Republic of China, Email sydtzhangqiang@163.comBackground: Brucellosis is a zoonotic disease that can affect various organs, including the spine. Cervical spondylitis caused by Brucella is rare but can lead to significant morbidity if not diagnosed and treated promptly.Case Presentation: We report a case of a 46-year-old female who presented with intermittent high fever and intractable neck, shoulder, and back pain for two months. She was diagnosed with Brucella cervical spondylitis based on clinical manifestations, Rose-Bengal Plate Agglutination Test (RBPT, positive), and cervical MRI findings. She was treated with a combination of antibiotics for at least two weeks, followed by surgical intervention including abscess clearance, partial vertebral resection, and titanium mesh bone fusion. Real-time Polymerase Chain Reaction (RT-PCR) confirmed the presence of sheep Brucella DNA. The patient recovered well postoperatively with significant pain reduction and restoration of full mobility in the right upper limb.Conclusion: This case highlights the diagnostic value of RT-PCR and tissue biopsy in cervical brucellosis spondylitis. Our study found that anterior cervical subtotal corpectomy can restore cervical stability, clear abscess, and relieve spinal cord compression on the basis of drug treatment, with good clinical results.Keywords: Brucellosis, cervical spondylitis, anterior cervical subtotal corpectomy, RT-PCR, gam staining, case report

Jing Shang,1,* Qi Xia,1,* Yuji Sun,2 Hongtao Wang,2 Jia Chen,1 Yue Li,1 Feng Gao,2 Peihao Yin,1,3,4 Zeting Yuan1– 4 1Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, People’s Republic of China; 2Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People’s Republic of China; 3Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Shanghai, 200062, People’s Republic of China; 4The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zeting Yuan; Peihao Yin, Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, People’s Republic of China, Email yuan340202@163.com; yinpeihao@shutcm.edu.cnPurpose: Compared with traditional photothermal therapy (PTT, > 50°C), mild PTT (≤ 45°C) is a promising strategy for tumor therapy with fewer adverse effects. Unfortunately, its anti-tumor efficacy is hampered by thermoresistance induced by overexpression of heat shock proteins (HSPs). In our previous study, we found bufalin (BU) is a glycolysis inhibitor that depletes HSPs, which is expected to overcome thermotolerance of tumor cells. In this study, BU-loaded multifunctional nanoparticles (NPs) were developed for enhancing the mild PTT of colorectal cancer (CRC).Methods: Fe3O4 NPs coated with the polydopamine (PDA) shell modified with polyethylene glycol (PEG) and cyclic arginine-glycyl-aspartic peptide (cRGD) for loading BU (Fe3O4@PDA-PEG-cRGD/BU NPs) were developed. The thermal variations in Fe3O4@PDA-PEG-cRGD/BU NPs solution under different conditions were measured. Glycolysis inhibition was evaluated by measuring the glucose uptake, extracellular lactate, and intracellular adenosine triphosphate (ATP) levels. The cellular cytotoxicity of Fe3O4@PDA-PEG-cRGD/BU NPs was analyzed using a cell counting kit-8 assay, Calcein-AM/PI double staining, and flow cytometry in HCT116 cells. The magnetic resonance imaging (MRI) performance and anti-tumor therapeutic efficacy of Fe3O4@PDA-PEG-cRGD/BU NPs were evaluated in HCT116-tumor bearing mice.Results: Fe3O4@PDA-PEG-cRGD/BU NPs had an average diameter of 260.4± 3.5 nm, the zeta potential of – 23.8± 1.6 mV, the drug loading rate of 1.1%, which had good thermal stability, photothermal conversion efficiencies and MRI performance. In addition, the released BU not only killed tumor cells but also interfered with glycolysis by targeting the steroid receptor coactivator 3 (SRC-3)/HIF-1α pathway, preventing intracellular ATP synthesis, and combating HSP-dependent tumor thermoresistance, ultimately strengthening the thermal sensitivity toward mild PTT both in vitro and in vivo.Conclusion: This study provides a highly effective strategy for enhancing the therapeutic effects of mild PTT toward tumors. Keywords: mild photothermal therapy, glycolysis metabolism, bufalin, HIF-1α, SRC-3

Yumei Wu,1– 3,* Chunhua Zeng,1– 3,* Jiajia Lv,1– 3 Hongyu Li,1– 3 Jie Gao,1– 3 Zhidong Liu,4 Zeli Yuan1– 3 1Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 2Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 3Guizhou International Scientific and Technological Cooperation Base for Medical Photo-Theranostics Technology and Innovative Drug Development, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 4Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhidong Liu, Tianjin University of Traditional Chinese Medicine, No. 10 Poyanghu Road, Tianjin, Jinghai District, 301617, People’s Republic of China, Email lonerliuzd@163.com Zeli Yuan, Zunyi Medical University, Zunyi, 563000, People’s Republic of China, Email zlyuan@zmu.edu.cnBackground: Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly because of increased toxicity from drug interactions and challenges in achieving the desired spatial and temporal distribution of drug delivery. Optimizing synergistic drug combination ratios to ensure uniform targeting and distribution across space and time, particularly in vivo, is a significant challenge. In this study, cRGD-coated liposomes encapsulating optimized synergistic cepharanthine (CEP; a chemotherapy drug) and IR783 (a phototherapy agent) were developed for combined chemotherapy and photothermal therapy in vitro and in vivo.Methods: An MTT assay was used to evaluate the combination index of CEP and IR783 in five cell lines. The cRGD-encapsulated liposomes were prepared via thin-film hydration, and unencapsulated liposomes served as controls for the loading of CEP and IR783. Fluorescence and photothermal imaging were used to assess the efficacy of CEP and IR783 encapsulated in liposomes at an optimal synergistic ratio, both in vitro and in vivo.Results: The combination indices of CEP and IR783 were determined in five cell lines. As a proof-of-concept, the optimal synergistic ratio (1:2) of CEP to IR783 in 4T1 cells was evaluated in vitro and in vivo. The average diameter of the liposomes was approximately 100 nm. The liposomes effectively retained the encapsulated CEP and IR783 in vitro at the optimal synergistic molar ratio for over 7 d. In vivo fluorescence imaging revealed that the fluorescence signal from cRGD-CEP-IR783-Lip was detectable at the tumor site at 4 h post-injection and peaked at 8 h. In vivo photothermal imaging of tumor-bearing mice indicated an increase in tumor temperature by 32°C within 200 s. Concurrently, cRGD-CEP-IR783-Lip demonstrated a significant therapeutic effect and robust biosafety in the in vivo antitumor experiments.Conclusion: The combination indices of CEP and IR783 were successfully determined in vitro in five cell lines. The cRGD-coated liposomes encapsulated CEP and IR783 at an optimal synergistic ratio, exhibiting enhanced antitumor effects and targeting upon application in vitro and in vivo. This study presents a novel concept and establishes a research framework for synergistic chemotherapy and phototherapy treatment. Keywords: drug delivery, liposomes, synergistic effects, phototherapy

Zhu Yuan,1,* Chunyan Chen,1,* Shuai Zeng,2 Zhen Wang,1 Shili Zhong1 1Department of Intensive Care Medicine, Army Medical Center of PLA, Chongqing, People’s Republic of China; 2Department of Laboratory Pathology, Unit 32280 of the People’s Liberation Army, Leshan City, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shili Zhong, Department of Intensive Care Medicine, Army Medical Center of PLA, No. 10 Changjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of China, Tel +86-18323087674, Email 805646578@qq.comBackground: Dermatomyositis (DM) represents a group of inflammatory myopathies, with TIF1-γ positive DM strongly associated with malignancies. Spontaneous muscular hematoma in DM patients is exceedingly rare and often prognosticates a severe clinical outcome, especially in the context of concurrent malignancy.Case Presentation: We describe a novel survival case of a patient with TIF1-γ positive DM and an underlying ovarian tumor who developed a spontaneous muscular hematoma. Despite the traditionally poor prognosis of these conditions, the patient survived through a comprehensive treatment regimen. This included targeted chemotherapy for ovarian cancer (Carboplatin and Paclitaxel), alongside corticosteroids, immunoglobulins, and immunosuppressants for DM, as well as component blood transfusions, coagulation correction therapy to control hematoma, and integrated management: nutritional support, lung function exercise, volume management.Results: The integrated treatment strategy stabilized the patient’s condition and resolved the hematoma, a significant achievement given the usual high mortality rate of such complications.Conclusion: This case underscores the importance of a multidisciplinary approach in the early diagnosis and treatment of TIF1-γ positive DM with complex comorbidities, including spontaneous muscular hematoma and ovarian cancer. It highlights the potential for favorable outcomes with aggressive and coordinated treatment strategies.Keywords: dermatomyositis, TIF1-γ, spontaneous muscular hematoma, ovarian cancer, multidisciplinary treatment, survival

Zihui Yuan,* Chao Du,* Yun You,* Jian Wang Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Wang, Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Tel +11-86-15902735929, Email jianwang1030@126.comPurpose: Iliac limb occlusion (ILO) is a serious complication of endovascular abdominal aneurysm repair (EVAR). This study aimed to identify predictive factors for ILO derived from aortoiliac morphology, endovascular procedure-related parameters, and aneurysmal remodeling characteristics.Patients and Methods: Patient demographics, pre-EVAR anatomical characteristics of the aneurysm, endovascular procedure details, and post-EVAR aneurysmal remodeling outcomes were analyzed and compared using univariate analysis. Statistically significant factors were subsequently subjected to Cox regression and Kaplan–Meier analyses.Results: Between January 2013 and April 2022, 66 patients were included in this study. Fourteen patients presented with ILO and were compared with 52 control patients with patent endograft limb over at least 1-year of follow-up. The tortuosity indices of the common iliac artery (CIA) and endograft iliac limb to vessel oversizing were significantly larger in the ILO group than in the patent endograft limb group. The CIA index of tortuosity ≥ 1.08, and endograft iliac limb to vessel oversizing ≥ 18.8% were independent predictors for ILO. During the follow-up of all patients, the proximal aortic neck and CIA diameters increased, aneurysm sac diameter decreased, and aortic neck and aortic length increased. The aortoiliac length increased over time in patients with patent endograft limb but not in patients with ILO. A change in the lowest renal artery-left iliac bifurcation distance ≦0.07 mm increased the risk of ILO.Conclusion: ILO is predisposed to occur when the CIA index of tortuosity ≥ 1.08 and endograft iliac limb to vessel oversizing ≥ 18.8% are present. Significant aortoiliac remodeling, including proximal aortic neck dilatation, neck straightening, aneurysmal sac regression, iliac artery enlargement, and aortic lengthening, occurs after EVAR. Aortoiliac elongation was observed in patients with patent endograft limb, but not in patients with ILO. ILO was associated with a change in the lowest renal artery–left iliac bifurcation from the postoperative measurements ≦ 0.07 mm.Keywords: abdominal aortic aneurysm, endovascular abdominal aneurysm repair, iliac limb occlusion, aortoiliac anatomy, aneurysmal remodeling, oversizing, aortoiliac tortuosity

Zhen Yuan,1,2 Fan Zhang,3 Zhiguang Li,1,2 Hua Wei1,2 1School of Economics and Management, Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of China; 2Key Laboratory of Data Science & Innovative Development of Traditional Chinese Medicine, Philosophy and Social Sciences of Anhui Province, Hefei, Anhui, People’s Republic of China; 3School of Finance, Nanjing Agricultural University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Zhiguang Li; Hua Wei, Email lizhiguang0731@163.com; weihua@ahtcm.edu.cnBackground: A linchpin to realizing the internal circulation (referring to the domestic cycle of production, distribution and consumption) is reducing residents’ saving rate and expanding the domestic needs. However, rural residents in China demonstrate a strong propensity to save money.Methods: In light of practical characteristics of urban-rural health integration promoted in different places, the three-phase data (from 2014 to 2018) and the dual difference-in-differences model of the China Labor-force Dynamics Survey (CLDS) are used to empirically investigate the impact of urban-rural health insurance integration on rural household savings.Results: Research reveals that urban-rural health integration can reduce the health risks and medical risks facing rural households, thus weakening the motivation of precautionary savings. The analysis of heterogeneity reveals that the integration of urban-rural health insurance significantly influences the savings rates of households headed by older individuals, particularly women, with lower levels of educational attainment. Besides, the single-tier health insurance system can have a more significant impact, whereas the multi-tier insurance system may not significantly affect the savings rate.Conclusion: Based on the aforesaid research conclusions, this article believes that in order to reduce the savings rate of rural households and expand consumption, the health insurance system should be further improved.Keywords: urban-rural health insurance integration, rural household, savings rate, health risks, medical risks

XiaoYing Yang, Mengda Wei, YanQing Huang, Xi Yang, ZhenMin Yuan, JunJie Huang, JunRen Wei, Lei Tian Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Lei Tian, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China, Email tianlei@stu.gxmu.edu.cnBackground: Stomach adenocarcinoma (STAD) presents a challenge given its advanced stage at diagnosis and poor prognosis. Integrin subunit alpha 11 (ITGA11) encodes alpha integrin and has been implicated in promoting tumorigenesis and development by participating in cell proliferation and invasion. However, the precise mechanism of ITGA11 in STAD remains unclear.Methods: The differences in ITGA11 expression levels between 375 gastric cancer samples and 32 paracancerous tissue samples from the Cancer Genome Atlas (TCGA) database were examined. The relationship between ITGA11 expression and clinical features and ITGA11 diagnostic and prognostic value were evaluated using the chi-square test and receiver operating characteristic (ROC) assay. Differentially expressed genes were identified based on ITGA11 expression. Subsequently, functional enrichment analyses were conducted using Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis. Furthermore, immune infiltration and the expression of ITGA11-associated immune checkpoints in patients with tumors were assessed using CIBERSORT, single-sample gene set enrichment analysis, and the TIMER database. Drug sensitivity associated with ITGA11 expression was analyzed using the R oncoPredict package to guide treatment decisions. Finally, the difference in ITGA11 expression between cancer tissue and the adjacent tissues was validated using quantitative PCR (qPCR) and immunohistochemistry.Results: The gastric cancer tissue had significantly upregulated ITGA11 expression compared to paracancerous tissues. ITGA11 demonstrated robust diagnostic and prognostic value in gastric cancer (GC) and was an independent risk factor for adverse outcomes. The patients with STAD with elevated ITGA11 expression levels had heightened immune cell infiltration and increased immune checkpoint marker expression. Notably, patients with increased ITGA11 expression demonstrated reduced responsiveness to oxaliplatin and afatinib.Conclusion: The results indicated the pivotal role of ITGA11 in shaping the tumor immune microenvironment, ultimately establishing ITGA11 as an immune-related prognostic predictor within the intricate landscape of STAD.Keywords: ITGA11, stomach adenocarcinoma, bioinformatics analysis, immune infiltration, prognosis

Yushen Jin,1 Zhongquan Cheng,2 Zhu Yuan,2 Yang Du,3 Jie Tian,3 Bing Shao1,4 1Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Centre for Disease Prevention and Control, Beijing, 100013, People’s Republic of China; 2Department of General Surgery, Capital Medical University, Beijing Friendship Hospital, Beijing, 100050, People’s Republic of China; 3CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, People’s Republic of China; 4College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People’s Republic of ChinaCorrespondence: Bing Shao; Jie Tian, Email shaobingch@sina.com; jietian@ia.ac.cnPurpose: Liver cancer is considered as the third leading cause of cancer-related deaths, with hepatocellular carcinoma (HCC) accounting for approximately 90% of liver cancers. Improving the treatment of HCC is a serious challenge today. The primary objective of this study was to construct SP94-Fe3O4@ICG&DOX nanoparticles and investigate their potential diagnosis and treatment effect benefits on HCC.Methods: Firstly, we synthesized and characterized SP94-Fe3O4@ICG&DOX nanoparticles and confirmed their in vitro release behavior, photothermal and photodynamic performance. Moreover, the in vivo imaging capability was also observed. Finally, the inhibitory effects on Hepa1-6 in vitro and in vivo were observed as well as biosafety.Results: SP94-Fe3O4@ICG&DOX nanoparticles have a size of ~22.1 nm, with an encapsulation efficiency of 45.2% for ICG and 42.7% for DOX, showing excellent in vivo MPI and fluorescence imaging capabilities for precise tumor localization, and synergistic photo-chemotherapy (pH- and thermal-sensitive drug release) against tumors under irradiation. With the assistance of a fluorescence molecular imaging system or MPI scanner, the location and contours of the tumor were clearly visible. Under a constant laser irradiation (808 nm, 0.6 W/cm2) and a set concentration (50 μg/mL), the temperature of the solution could rapidly increase to ~45 °C, which could effectively kill the tumor cells. It could be effectively uptaken by HCC cells and significantly inhibit their proliferation under the laser irradiation (100% inhibition rate for HCC tumors). And most importantly, our nanoparticles exhibited favorable biocompatibility with normal tissues and cells.Conclusion: This versatile agent can serve as an intelligent and promising nanoplatform that integrates multiple accurate diagnoses, precise positioning of cancer tissue, and effective coordination with synergistic tumor photodynamic therapy. Keywords: porous hollow structure, magnetic particle imaging, fluorescence imaging, synergistic treatment, theranostics

Xinyu Li,1,2,* Yedi Cao,1,* Nan Gu,1 Zhenfang Yuan1 1Department of Endocrinology, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Nan Gu, Email nan.gu@pkufh.cnAbstract: Renal cysts and diabetes syndrome (RCAD) is a rare disease caused by abnormalities in the HNF1B gene, which often leads to dysfunction in the renal, genital tracts, and pancreas. In this report, we present a rare case of a 27-year-old female with muscle mass loss who experienced a delayed diagnosis of RCAD. The patient had been misdiagnosed as “type 1 diabetes” for a long period. Her main clinical manifestations included muscle loss, renal magnesium loss, and an incomplete longitudinal uterus. Ultimately, the diagnosis of RCAD syndrome was confirmed through genetic testing. Reduction of muscle mass, although rarely reported, can progress to sarcopenia. Therefore, early intervention should be strongly emphasized. Furthermore, in future research, it is crucial to explore the mechanisms and relationships underlying these patients and their unusual manifestations.Keywords: muscle loss, special type diabetes, maturity-onset diabetes of the young type 5, 17q12 deletion syndrome, renal cysts and diabetes syndrome, case report

Yue Wu,1,* Zhiqun Mao,2,* Fengwei Cui,2 Jie Fan,1 Zhouling Yuan,3 Li Tang2 1Department of Geriatric Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi, Jiangsu, People’s Republic of China; 2Department of Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi, Jiangsu, People’s Republic of China; 3Department of Psychiatry, Huishan No. 2 People’s Hospital, Wuxi, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Tang, Department of Psychiatry, The Affiliated Mental Health Center of Jiangnan University, 156 Qianrong Road, Wuxi, 214151, People’s Republic of China, Tel +86 510 83219318, Fax +86 510 830 12201, Email 839223872@qq.comBackground and Purpose: Subjective cognitive decline (SCD) is recognized as a preclinical indicator of Alzheimer’s disease (AD), and this stage provides a valuable time window for ultra-early intervention in AD. The aim of this study was to investigate the neurocognitive characteristics of SCD and its correlation with objective cognition, negative emotion and sleep quality in Chinese elderly.Methods: A total of 1200 volunteers aged 60 and older underwent Brief Elderly Cognitive Screening Inventory, Quick Cognitive Screening Scale for the Elderly, Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Pittsburgh Sleep Quality Index and Core Neuropsychological Test. According to the examination results, the participants were divided into healthy control (HC) and SCD groups. The neurocognitive function of SCD and its relationship with objective cognition, negative emotion and sleep quality were analyzed.Results: Compared with the HC group, the SCD group had similar global cognitive function but slightly impaired neurocognitive function. After adjusting for confounding factors such as age, sex, marriage, education and chronic disease, neurocognitive function (Picture-Symbol Matching: OR=0.167, 95% CI: 0.105– 0.266; Word Stem Completion: OR =0.260, 95% CI: 0.131– 0.514; Trail Making Test: OR=0.315, 95% CI: 0.178– 0.560; Picture Recall: OR =0.278, 95% CI: 0.122– 0.636), negative emotion (sub-depressive symptoms: OR=2.287, 95% CI: 1.483– 3.527; sub-anxiety symptoms: OR=1.663, 95% CI: 1.079– 2.563), and poor sleep quality (OR=2.138, 95% CI: 1.571– 2.909) were significantly correlated with the occurrence of SCD.Conclusion: The study illustrates that SCD is closely related to objective cognition, negative emotion and sleep quality. Clinical evaluation and follow-up of SCD should fully account for these factors.Keywords: subjective cognitive decline, cognitive function, negative emotions, sleep quality, Alzheimer′s disease

Jihui Lu, Zhijia Wang, Desheng Cai, Xiaoyu Lin, Xuemei Huang, Zhihua Yuan, Yaozhi Zhang, Haimin Lei, Penglong Wang School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of ChinaCorrespondence: Penglong Wang, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email wpl581@126.com Haimin Lei, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email hm_lei@126.comBackground: Deaths from bacterial infections have risen year by year. This trend is further aggravated as the overuse antibiotics and the bacterial resistance to all known antibacterial agents. Therefore, new therapeutic alternatives are urgently needed.Methods: Enlightenment the combination usage of traditional herb medicine, one carrier-free binary nanoparticles (GA-BBR NPs) was discovered, which was self-assembled from gallic acid and berberine through electrostatic interaction, π-π stacking and hydrophobic interaction; and it could be successfully prepared by a green, cost-effective and “one-pot” preparation process.Results: The nanoparticles exhibited strong antibacterial activity and biofilm removal ability against multidrug-resistant S. aureus (MRSA) by downregulating mRNA expression of rpsF, rplC, rplN, rplX, rpsC, rpmC and rpsH to block bacterial translation mechanisms in vitro and in vivo, and it had well anti-inflammatory activity and a promising role in promoting angiogenesis to accelerate the wound healing on MRSA-infected wounds model in vivo. Additionally, the nanoparticles displayed well biocompatibility without cytotoxicity, hemolytic activity, and tissue or organ toxicity.Conclusion: GA-BBR NPs originated from the drug combination has potential clinical transformation value, and this study provides a new idea for the design of carrier-free nanomedicine derived from natural herbals.Graphical Abstract: Keywords: carrier-free binary self-assemblies, natural herbal ingredients, antibacterial, wound healing, anti-inflammatory, angiogenesis

Xiaonan Sun,1 Zhichao Yuan,1 Lu Zhang,1 Min Ren,2 Jing Yang,2 Yidan Xu,1 Jiqing Hao1 1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China; 2Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of ChinaCorrespondence: Jiqing Hao, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230022, People’s Republic of China, Email haojiqing@ahmu.edu.cnPurpose: Elucidation of the oncogenic role of SLC35A2 in human tumors and the potential function and clinical significance in breast cancer.Methods: Pan-cancer analysis was performed via various bioinformatics tools to explain the pathogenic role of SLC35A2. A prognostic nomogram was also developed based on the SLC35A2 expression and clinicopathological characteristics in breast cancer patients. In addition, the role of SLC35A2 was validated in breast cancer by in vivo and in vitro experiments.Results: SLC35A2 expression is increased in 27 tumor types, and its high expression is substantially correlated with poor prognosis in patients with a variety of cancers. Receiver operating characteristic (ROC) curves showed that SLC35A2 expression levels could accurately distinguish most tumor tissues from normal tissues. High SLC35A2 expression was linked to increased immune infiltration in myeloid-derived suppressor cells (MDSC), as well as immune checkpoints, ferroptosis-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI). SLC35A2 may be involved in tumorigenesis by regulating the glycosylation process. Furthermore, multivariate Cox analysis showed that SLC35A2 was an independent prognostic factor for breast cancer. And the nomogram model had good predictive accuracy for the prognosis of breast cancer patients. Meanwhile, cellular experiments demonstrated that knockdown of SLC35A2 could significantly inhibit the proliferation, migration and invasion of breast cancer cells, while increasing the protein level of E-cadherin and decreasing N-cadherin. A nude mouse xenograft model showed that inhibition of SLA35A2 expression could significantly inhibit tumor growth.Conclusion: SLC35A2 has good diagnostic and prognostic values in multiple cancers and is closely related to tumor immune infiltration. In addition, SLA35A2 as an oncogene in breast cancer may be involved in the progression of epithelial mesenchymal transition (EMT).Keywords: SLC35A2, pan-cancer, breast cancer, prognostic, tumor microenvironment, EMT

Xiaojia Liu,1,2 Caiyan Lin,1 Wenfei Zhong,1 Zhongwen Yuan,1 Pengke Yan,1 Shixia Guan2 1Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Pengke Yan; Shixia Guan, Email gysyypk@126.com; drguan@gzucm.edu.cnBackground: The activation of lymphatic vessel function is the crux to resolving atherosclerosis (AS), a chronic inflammatory disease. Rapamycin (RAPA) recently has attracted considerable attention as a potent drug to induce atherosclerotic plaque attenuation. The objective of this work was to develop a ligand-decorated, RAPA-loaded liposome for lymphatic-targeted delivery of drugs to improve abnormal lymphatic structure and function, resulting in highly effective regression of atherosclerotic plaques.Methods: Hyaluronic acid-decorated, RAPA-loaded liposomes (HA-RL) were fabricated by emulsion-solvent evaporation. The average size, zeta potential, entrapment efficiency were characterized, and the stability and drug release in vitro were investigated. Furthermore, the in vitro and in vivo lymphatic targeting ability were evaluated on lymphatic endothelial cells and LDLR−/− mice, and the efficiency of this nano-system in inducing the attenuation of atherosclerotic plaques was confirmed.Results: HA-RL had a size of 100 nm, over 90% drug encapsulation efficiency, the storage stability was distinguished, demonstrating a slow release from the lipid nano-carriers. The mean retention time (MRT) and elimination half-life (t1/2β) achieved from HA-RL were 100.27± 73.08 h and 70.74± 50.80 h, respectively. HA-RL acquired the most prominent efficacy of lymphatic-targeted delivery and atherosclerotic plaques attenuation, implying the successful implementation of this novel drug delivery system in vivo.Conclusion: HA-RL exhibited the most appreciable lymphatic targeting ability and best atherosclerotic plaques attenuation efficiency, opening a new paradigm and promising perspective for the treatment of arteriosclerosis.Keywords: rapamycin, hyaluronic acid, lymphatic targeting, arteriosclerosis, liposomes

Wen Wen,1 Zhanyi Zhang,2 Jianqing She,2 Xiaofang Bai,3 Yan Wu,2 Li Gao,2 Juan Zhou,2,4,5 Zuyi Yuan2,4,5 1Department of Ultrasound, Clinical Medical College, First Affiliated Hospital of Chengdu Medical College, Chengdu, People’s Republic of China; 2Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 3Department of Ultrasound, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 4Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 5Key Laboratory of Molecular Cardiology, Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Juan Zhou; Zuyi Yuan, Email zj.7332@mail.xjtu.edu.cn; zuyiyuan@mail.xjtu.edu.cnBackground: White blood cell (WBC) indices are strongly associated with cardiovascular disease, but data on the prognostic values of these parameters in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI) are sparse. The current study aimed to investigate the relationship between baseline WBC indices levels and the incidence of heart failure (HF) in ACS patients after PCI and explore the predictive values over a 2-year follow-up period.Methods: A total of 416 consecutive ACS patients treated with PCI were enrolled and received a median of 27.7 months follow-up. Univariate and multivariate Cox regression analyses and the receiver operating characteristic (ROC) curves were performed.Results: Baseline lymphocyte (LYMPH) count, eosinophil (EO) count and eosinophil percentage (EO %) were higher in patients who experienced HF over a 2-year follow-up. In multivariate Cox proportional hazards analysis, LYMPH count, EO count and EO % were independently associated with the occurrence of HF (hazard ratio [HR] = 12.876, P = 0.025; HR = 16.625, P = 0.004; HR = 1.196, P = 0.031, respectively). The area under the ROC curve of baseline EO count predicting the occurrence of HF in ACS patients following PCI was 0.625 (P = 0.037). For patients aged 60 years and above, who had PCI or history of coronary artery bypass grafting, the higher EO count, the higher the risk of HF.Conclusion: Elevated baseline LYMPH count, EO count and EO % were independently associated with the incidence of HF in ACS patients following PCI, suggesting that WBC indices might be available, simple, and cost-efficient biomarkers with predictive value, especially for patients aged more than 60 years.Keywords: heart failure, acute coronary syndrome, lymphocytes, eosinophils, independent predictive factors

Introduction Over half of the populations with knee osteoarthritis (OA) have obesity. These individuals have many other shared metabolic risk factors. Metformin is a safe, inexpensive, well-tolerated drug that has pleiotropic effects, including structural protection, anti-inflammatory and analgesic effects in OA, specifically the knee. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether metformin reduces knee pain over 6 months in individuals with symptomatic knee OA who are overweight or obese.Methods and analysis One hundred and two participants with symptomatic knee OA and overweight or obesity will be recruited from the community in Melbourne, Australia, and randomly allocated in a 1:1 ratio to receive either metformin 2 g or identical placebo daily for 6 months. The primary outcome is reduction of knee pain [assessed by 100 mm Visual Analogue Scale (VAS)] at 6 months. The secondary outcomes are OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) responder criteria [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and participant’s global assessment (VAS)] at 6 months; change in knee pain, stiffness, function using WOMAC at 6 months and quality of life at 6 months. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups.Ethics and dissemination Ethics approval has been obtained from the Alfred Hospital Ethics Committee (708/20) and Monash University Human Research Ethics Committee (28498). Written informed consent will be obtained from all the participants. The findings will be disseminated through peer-review publications and conference presentations.Trial registration number ACTRN12621000710820 .

Objective: To investigate the variation in the distribution and the natural history of hand pain over 6 weeks in individuals with symptomatic hand osteoarthritis. Design: Patient-reported outcome data were collected at baseline and weekly for 6 weeks from community-based participants enrolled in a randomised controlled trial. Participants were grouped based on location of significant pain (Visual Analogue Scale, VAS≥40/100 ​mm) (both carpometacarpal (CMC) and interphalangeal (IP), CMC only, and IP only). Results: At baseline, of the 106 participants, 55(51.9 %) had pain in both CMC and IP joints, 28(26.4 %) in IP joints only, and 16(15.1 %) in CMC joint only. Those with CMC and IP pain had significantly higher VAS pain [68.1 (2.6) vs 59.3 (3.5) vs 51.2 (4.7)]; Australian Canadian Osteoarthritis Hand Index, (AUSCAN) pain [290.1 (15.7) vs 225.3 (21.2) vs 237.9 (28.4)], stiffness [57.1 (3.7) vs 44.6 (5.0) vs 32.2 (6.7)] and functional limitation [527.5 (30.9) vs 356.0 (41.7) vs 433.3 (55.7)]; and pain sensitization [PainDETECT score 11.1 (1.1) vs 8.1 (1.8) vs 5.8 (1.9)] compared to those with IP or CMC only pain, respectively. All groups showed improvement in outcomes over 6 weeks without significant inter-group differences. Conclusion: In a population with significant hand pain, pain in both CMC and IP joints was most common and identified a more severe phenotype than pain in IP or CMC only with higher pain, more functional limitation and pain sensitization. These data have the potential to inform clinical management of patients with hand pain and patient selection in clinical trials.

Obesity is the major modifiable risk factor for osteoarthritis (OA). A major focus of management in OA is weight loss. Although we live in an obesogenic environment, obesity has a predominantly genetic and epigenetic basis. This explains a person's weight set point which is defended by biological mechanisms making weight loss difficult to achieve and maintain long term, regardless of the methods used. Significant weight regain occurs after weight loss, with weight tending to return to pre-treatment levels after cessation of interventions including the glucagon-like peptide-1 (GLP-1) agonists. An area that has received little attention is the slow, insidious weight creep of 0.5–1 kg/year over adulthood that sees individuals relentlessly increase weight. There is evidence that low intensity, personalised lifestyle interventions can prevent this weight creep, providing patients with achievable goals. In this narrative review, we examine the evidence for weight loss in OA, the biological mechanisms that make weight loss difficult to achieve and maintain and the potential negative impacts on patients. We review the evidence for preventing weight gain, the improvement in patient outcomes and the potential for significant healthcare savings through reduced knee replacements. We propose a combined approach of weight loss when indicated, together with targeting weight creep across adult years and the potential role of metformin. Implementing these combined approaches is likely to be more effective in improving patient related outcomes, reducing joint damage and healthcare costs, than our current focus on achieving weight loss in OA.

Yue Fang,1,2 Zhichao Yuan,1 Hao Zhang,1 Peng Wang,3 Jiqing Hao1 1Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Intern of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences (CAS), Hefei, People’s Republic of China; 3Department of Anesthesiology, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Jiqing Hao, Email haojiqing@ahmu.edu.cnPurpose: Heat shock protein 90α (HSP90α) is highly expressed in tumors, and predicts tumor progression. This study analyzed the correlation between the expression level of HSP90α in the serum and the prognosis of patients with lung adenocarcinoma.Patients and methods: The medical records of patients with 228 lung adenocarcinoma from September 2015 to December 2021 were analyzed. HSP90α expression in the patients’ serum was detected by ELISA and the cut-off value (93.76 ng/mL) was determined according to the ROC curve, then the patients were divided into high- and low-level groups. The differences in the medical records of the two groups were compared using the X2 test, and Univariate and multivariate Cox regression analyses showed that serum HSP90α level were independent risk factors for both PFS and OS (P < 0.05).Results: HSP90α was positively correlated with TNM staging (P < 0.01) by One-way analysis of variance. The results of the correlation analysis and the Kaplan–Meier survival curve showed that the expression levels of HSP90α and CEA of patients were positively correlated (R=0.54, P < 0.001), and patients with high HSP90α and CEA levels had the worst OS (P < 0.001).Conclusion: HSP90α expression is negatively correlated with the prognosis of patients with lung adenocarcinoma and is a potential prognostic marker.Keywords: heat shock protein 90α, lung adenocarcinoma, prognosis, CEA

Zheng Yuan,1 Lixia Gao,2 Meijie Zheng,3 Xiaobo Ye,4 Sujuan Sun1 1Department of Nursing, Hebei General Hospital, Shijiazhuang, 050000, People’s Republic of China; 2Department of Cardiovascular Medicine for the Elderly, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Gastroenterology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 4Second Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Sujuan Sun, Department of Nursing, Hebei General Hospital, No. 348, Heping West Road, Shijiazhuang, Hebei, People’s Republic of China, Tel +86-311-85988114, Email sunsujuan1818@163.comObjective: To explore the effect of multimodal health education combined with a feedback method in perioperative patients with lung cancer.Methods: A total of 200 lung cancer patients were divided into the observation group and the control group. The observation group adopted the multimodal health education combined with the feedback method, and the control group adopted the conventional health education model. The postoperative extubation time, length of hospital stay, time to first leaving the bed, postoperative exercise compliance, emotional-distress index and patient satisfaction were compared between the two groups.Results: The postoperative extubation time (2.80 ± 1.03 days), the emotional-distress index (8.26 ± 3.01) and the time to first leaving the bed (23.74 ± 11.87 h) were all lower in the observation group than in the control group, with a statistically significant difference (P < 0.05). The postoperative exercise compliance (49.69 ± 3.60) and patient satisfaction (98.32 ± 1.66) values were higher in the observation group than in the control group, with statistically significant differences (P < 0.05).Conclusion: Multimodal health education combined with the feedback method can improve the postoperative exercise compliance of lung cancer patients, reduce their postoperative rehabilitation time and improve their postoperative psychological state and satisfaction, which is in line with the concept of promoting the enhanced recovery of lung cancer patients.Keywords: lung cancer, enhanced recovery after surgery, feedback method, multimodal health education

Siyuan Ma,1,&ast; Yali Gong,1,&ast; Xiaoqiang Luo,1,&ast; Yuan Peng,2 Cheng Zhang,1 Xiaorong Zhang,1 Xiaohong Hu,1 Peng Tang,3 Zhiqiang Yuan,1 Gaoxing Luo,1 Haisheng Li1 1State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 2Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Clinical Laboratory, the Second Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haisheng Li, Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Street, Shapingba District, Chongqing, 400038, People’s Republic of China, Tel +86-023-68765952, Email lee58427@163.comBackground: Elizabethkingia meningoseptica infections have gradually emerged as life-threatening nosocomial infections worldwide, accompanied by increasing incidence, multidrug resistance and poor outcomes. However, the epidemiology and clinical features of E. meningoseptica infection are still limited in mainland China.Methods: Patients with E. meningoseptica infections from 2011 to 2019 in southwestern China were retrospectively analyzed. The clinical features, infection patterns and outcomes were extracted from medical records and analyzed. A comprehensive systematic review was performed in accordance with PRISMA guidelines from conception to August 23, 2021.Results: Ninety-two patients were ultimately included, with the prevalence rapidly rising from 0 in 2011 to 0.19 per 1000 inpatients in 2019. A total of 93.48% of E. meningoseptica isolates were multidrug resistant, including 100% resistance to carbapenem. Furthermore, 75% of E. meningoseptica infections were concomitant with other pathogens. The mortality of our cohort was 36.96%, with risk factors for mechanical ventilation (OR=9.51, P=0.004), male sex (OR=0.27, P=0.031) and more concomitant pathogens. After propensity score matching, central venous catheters, exposure to carbapenem and antifungal drugs, and underlying tumors were associated with E. meningoseptica infection. Sixteen articles were also summarized, with reported mortality rates ranging from 11.0% to 66.6%. Blood and respiratory tract were the common sources. Piperacillin/tazobactam, trimethoprim/sulfamethoxazole, fluoroquinolone and minocycline were the most sensitive antibiotics. Inappropriate antibiotic treatment was the most commonly reported risk factor for mortality.Conclusion: Nosocomial infection with E. meningoseptica has become an emerging problem with high mortality in southwestern China. Inappropriate antibiotic treatment and central venous catheters are risk factors for infection and death and should receive adequate attention.Keywords: meningoseptica, nosocomial infection, epidemiology, risk factor, multidrug resistance, infection control

Objective: To examine the efficacy and safety of topical corticosteroid over 6 weeks in patients with symptomatic hand osteoarthritis. Design: In a randomized, double-blind, placebo-controlled trial, community-based participants with hand osteoarthritis were randomly assigned (1:1) to topical Diprosone OV (betamethasone dipropionate 0.5 ​mg/g in optimised vehicle, n=54) or placebo (plain paraffin, n=52) ointment to painful joints 3 times daily for 6 weeks. Primary outcome was pain reduction [assessed by 100 ​mm visual analogue scale (VAS)] at 6 weeks. Secondary outcomes included changes in pain and function using the Australian Canadian Osteoarthritis Hand Index (AUSCAN), Functional Index for Hand Osteoarthritis (FIHOA), and Michigan Hand Outcomes Questionnaire (MHQ) at 6 weeks. Adverse events were recorded. Results: Of 106 participants (mean age 64.2 years, 85.9% female), 103 (97.2%) completed the study. Change in VAS at 6 weeks was similar in the Diprosone OV and placebo groups (−19.9 vs. −20.9, adjusted difference 0.6, 95% CI -8.9 to 10.2). There were no significant between-group differences in change in AUSCAN pain [adjusted difference 25.8 (−16.0 to 67.5)], AUSCAN function [21.2 (−55.0 to 97.4)], FIHOA [-0.1 (−1.7 to 1.5)], or MHQ [-1.2 (−6.0 to 3.6)]. Incidence of adverse events was 16.7% in Diprosone OV and 19.2% in placebo group. Conclusions: Topical Diprosone OV ointment, although well-tolerated, was no better than placebo in improving pain or function over 6 weeks in patient with symptomatic hand osteoarthritis. Future studies should consider examining joints with synovitis and whether delivery approaches enhancing transdermal penetration of corticosteroids into joints are effective in hand osteoarthritis. Trial registration: ACTRN 12620000599976. Registered May 22, 2020.

Yousheng Mo,1,&ast; Wei Liu,2,&ast; Piaoxue Liu,2 Qiao Liu,3 Zhongyu Yuan,4 Qi Wang,2 Dongsheng Yuan,2 Xiao-Jia Chen,3 Tongkai Chen2 1The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 2Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, People’s Republic of China; 4Department of Medical Oncology, Sun Yat-Sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Jia Chen; Tongkai Chen, Email xiaojiachen@um.edu.mo; chentongkai@gzucm.edu.cnBackground: Breast cancer (BC) has the highest global prevalence among all malignancies in women and the second highest prevalence in the overall population. Paclitaxel (PTX), a tricyclic diterpenoid, is effective against BC. However, its poor solubility in water and the allergenicity of its dissolution medium limited its clinical application.Methods: In this work, we established a multifunctional graphene oxide (GO) tumor-targeting drug delivery system using nanosized graphene oxide (nGO) modified with D-tocopherol polyethylene glycol succinate (TPGS) and arginine-glycine-aspartic acid (RGD) for PTX loading.Results: The obtained RGD-TPGS-nGO-PTX was 310.20± 19.86 nm in size; the polydispersity index (PDI) and zeta potential were 0.21± 0.020 and − 23.42 mV, respectively. The mean drug loading capacity of RGD-TPGS-nGO-PTX was 48.78%. RGD-TPGS-nGO-PTX showed satisfactory biocompatibility and biosafety and had no significant toxic effects on zebrafish embryos. Importantly, it exerted excellent cytotoxicity against MDA-MB-231 cells, reversed multi-drug resistance (MDR) in MCF-7/ADR cells, and showed significant anti-tumor efficacy in tumor-bearing nude mice.Conclusion: These findings strongly suggested that the multifunctional GO tumor-targeting drug delivery system RGD-TPGS-nGO-PTX could be used in clinical settings to improve PTX delivery, reverse MDR and increase the therapeutic efficacy of BC treatment.Keywords: breast cancer, paclitaxel, targeted delivery, multidrug resistance

Shangwen Jing,1,&ast; Yantong Lu,1,2,&ast; Jing Zhang,1 Yan Ren,1,2 Yousheng Mo,3 Dongdong Liu,3 Lining Duan,4 Zhongyu Yuan,5 Changjun Wang,2 Qi Wang1 1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, People’s Republic of China; 3The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Medical Oncology, Sun Yat-Sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changjun Wang; Qi Wang, Email gzwchj@126.com; wangqi@gzucm.edu.cnIntroduction: Breast cancer (BC) is the leading female malignancy, with one million new cases diagnosed worldwide per year. However, the current treatment options for BC patients have difficulty achieving satisfactory efficacy. Ferroptosis is a new mode of regulated cell death that plays a key role in the inhibition of tumorigenesis. Levistilide A (LA), as an active compound extracted from Chuanxiong Rhizoma, might prevent the development of tumors by regulating the critical cellular processes of ferroptosis.Methods: In this study, the underlying mechanisms of LA on ferroptosis in BC were explored in vitro. The effect of LA on the viability and mitochondrial function of BC cells was determined. Moreover, the effect of LA on the expression levels of key molecules involved in ferroptosis and the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway was evaluated.Results: LA significantly reduced cell viability and damaged the mitochondrial structure and function of BC cells in a dose-dependent manner. Furthermore, LA treatment markedly enhanced reactive oxygen species (ROS)-induced ferroptosis by activating the Nrf2/HO-1 signaling pathway.Conclusion: These findings suggest that LA may be a potential lead compound for breast cancer therapy by inducing ferroptosis in tumor cells.Keywords: breast cancer, levistilide A, ferroptosis, Nrf2/HO-1 signaling pathway

Lu Zhang,1 Yue Fang,1 Jianghao Xing,1 Hao Cheng,2 Xiaonan Sun,1 Zhichao Yuan,1 Yidan Xu,1 Jiqing Hao1 1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Jiqing Hao, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 81 Meishan Road, Hefei, 230022, People’s Republic of China, Tel +86 13965029739, Email haojiqing@ahmu.edu.cnPurpose: This study aimed to analyze the association between venous thromboembolism (VTE) and inflammatory markers like systemic immune-inflammation index (SII) and prognosis nutritional index (PNI), and to evaluate their efficacy for the diagnosis of VTE in patients with gastrointestinal malignancies.Patients and Methods: A total of 1326 patients with the initial diagnosis of gastrointestinal cancer in the First Affiliated Hospital of Anhui Medical University (AHMU) were enrolled in the training cohort. Univariate and multivariate analysis was used to pinpoint independent predictors of VTE, which were eventually visualized as the nomogram models. The Akaike Information Criterion (AIC) was used to screen the best model. The receiver operating characteristic curve (ROC) and the clinical decision curve analysis (DCA) were utilized to evaluate the models’ predictive performance in the training queue and another external sample of 250 patients at the Second Affiliated Hospital of AHMU.Results: A total of 476 patients were complicated with VTE in the training cohort. Multifactorial analysis of clinical characteristics and inflammatory markers showed that PNI, SII, age, tumor location, and therapy were independent risk factors of VTE, visualized as model A. Another model B was constructed by adding coagulation markers to the previous analysis. Model B was the best prediction model with the minimum AIC value, followed by model A with an AUC of 0.806 (95% CI 0.782∼ 0.830) which was similar to model B’s 0.832 (95% CI 0.810∼ 0.855) but significantly higher than the currently widely used Khorana score’s 0.592 (95% CI 0.562∼ 0.621) and the CATS score’s 0.682 (95% CI 0.653∼ 0.712). The external verification yielded similar findings, with the AUC being 0.792 (95% CI 0.734∼ 0.851), 0.834 (95% CI 0.778∼ 0.890), 0.655 (95% CI 0.582∼ 0.729), and 0.774 (95% CI 0.699∼ 0.849) respectively. The DCA curves demonstrated that new models had excellent usefulness in screening patients with a high VTE risk.Conclusion: The SII and PNI were simple and viable inflammatory markers associated with VTE, and the nomogram based on them and clinical features had a meaningful clinical utility for VTE in patients with gastrointestinal malignancies.Keywords: venous thromboembolism, gastrointestinal cancers, inflammation, systemic immune-inflammation index, nomogram

Zhifei Hou,1,2 Zhihui Yuan,3 Hao Wang,4 Kang Chang,5 Yong Gao1 1Department of Pulmonary and Critical Care Medicine, Sinopharm Tongmei General Hospital, Datong, People’s Republic of China; 2China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Emergency, Chinese PLA General Hospital -Fourth Medical Center, Beijing, People’s Republic of China; 4School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Clinical Center for Pulmonary Infections, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Yong Gao; Zhifei Hou, Email tmzyyhx@163.com; houzhifei1898@126.comBackground: COPD is a respiratory disease caused by a combination of genetic and environmental factors. Polymorphism, as a genetic factor, can affect the susceptibility of the disease of COPD. In this study, we assessed the relationship between the polymorphisms of three genes and COPD risk in a Chinese Han population.Patients and Methods: A total of 376 patients diagnosed with COPD and 284 control subjects were enrolled in this study. Multivariate logistic regression analysis was used to analyze the association between three polymorphisms (SMAD4 rs10502913, IL-4 rs2070874, HSPA1L rs2227956) and COPD susceptibility.Results: The SMAD4 rs10502913 GG and AG genotype significantly increased COPD risk (adjusted OR = 2.235, 95% CI 1.198– 4.104; adjusted OR = 2.218, 95% CI 1.204– 4.151, respectively) compared with the AA genotype. In the stratification analyses, the GG genotype significantly increased the risk of COPD in subjects aged 60 and over (adjusted OR = 2.519, 95% CI 1.266– 5.015) and with a smoking history of less than 30 years (p=0.009; adjusted OR = 3.751; 95% CI 1.398– 10.062). This increased risk was more pronounced in the group of GOLD I and GOLD II (adjusted OR = 3.628, 95% CI 1.022– 12.885; adjusted OR = 2.394, 95% CI 1.004– 5.710, respectively). In addition, AG genotype was associated with an increased COPD risk in subjects aged 60 and over (adjusted OR = 2.599, 95% CI 1.304– 5.176) and in smokers (p=0.021; adjusted OR = 2.269; 95% CI 1.132– 4.548). This increased risk was more obvious in the group of GOLD III COPD (p=0.047; adjusted OR = 2.532; 95% CI 1.012– 6.336).Conclusion: Our present study indicated that the genotype GG and AG of SMAD4 rs10502913 are associated with an increased risk of COPD in a Chinese Han population. Further validation studies with large-scale populations are needed to confirm our findings.Keywords: COPD, chronic obstructive pulmonary disease, polymorphism, SMAD4 rs10502913, similar to mother against decapentaplegic 4, risk

Yuanming Xing,1,2 Chen Wang,1,2 Haoyu Wu,1,2 Yiming Ding,1,2 Siying Chen,3 Zuyi Yuan1,2 1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Zuyi Yuan, Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China, Email zuyiyuan@mail.xjtu.edu.cnPurpose: Left ventricular aneurysm (LVA) is a severe and common mechanical comorbidity with acute myocardial infarction (AMI) that can present high mortality and serious adverse outcomes. Accordingly, there is a need for early identification and prevention of patients at risk of LVA. The aim of this study was to develop and validate a risk prediction model for LVA among AMI patients in Northwest China.Methods: A total of 509 patients with AMI were retrospectively collected between January 2018 and August 2021. All patients were randomly divided into a training group (n=356) and a validation group (n=153). Potential risk factors for LVA were screened for predictive modelling using least absolute shrinkage and selection operator regression, multivariate logistic regression, clinical relevance, and represented by a comprehensive nomogram. Receiver operating characteristic curve, calibration curve, and decision-curve analysis (DCA) were used to assess the discrimination capacity, calibration, and clinical validity, respectively.Results: Seven predictors were finally identified for the establishment of prediction model, including age, cardiovascular disease history, left ventricular ejection fraction, ST-segment elevation, percutaneous coronary intervention history, mean platelet volume, and aspartate aminotransferase. The prediction model achieved acceptable areas under the curves of 0.901 (95% confidence interval [CI]=0.868– 0.933) and 0.908 (95% CI=0.861– 0.956) in the training and validation groups, respectively, and the calibration curves fit well in our model. The DCA result indicated that this nomogram exhibited a favorable performance in terms of clinical utility.Conclusion: An accurate prediction model for LVA development established, which can be applied to rapidly assess the risk of LVA in patients with AMI. Our findings will aid clinical decision-making to reduce the incidence of LVA in high-risk patients, and counteract adverse cardiovascular outcomes.Keywords: cardiovascular disease, acute myocardial infarction, left ventricular aneurysm, risk prediction model, adverse cardiovascular outcomes

He J, Guan J, Liao S, et al. Onco Targets Ther. 2021;14:1–13. We, the Editor and Publisher of Onco Targets and Therapy are retracting the published article. Since publication, concerns have been raised about the duplication of images in this article with those from other unrelated articles. Specifically, The image in Figure 1I, HOS, si-NC, has been duplicated with the image from Figure 2I, SW480, si-NC, from Luo X, Yue M, Li C, Sun D, Wang L. Long Non-Coding RNA LINC00239 Functions as a Competitive Endogenous RNA by Sponging microRNA-484 and Enhancing KLF12 Expression to Promote the Oncogenicity of Colorectal Cancer. Onco Targets Ther. 2020;13:12067–12081. https://doi.org/10.2147/OTT.S278582 (RETRACTED). The image from Figure 1I, Saos-2, si-CCDC144NL-AS1, and Figure 5D, HOS, si-CCDC144NL-AS1+anti-miR-490-3p, has been duplicated with the image from Figure, 4H, HCT116, si-C1QTNF1-AS1+NC inhibitor and Figure 1H, SW480, si-NC, respectively, from Jin S, Liu Y, Wang W, Li Z. Long Non-Coding RNA C1QTNF1 Antisense RNA 1 Upregulates Hexokinase 2 by Sponging microRNA-484 to Promote the Malignancy of Colorectal Cancer. Cancer Manag Res. 2020;12:12053–12066. https://doi.org/10.2147/CMAR.S262096 (RETRACTED). The image from Figure 1H, Saos-2, si-NC, has been duplicated with the image from Figure 1I, HCT116, si-NC from Liu H, Zhang X, Jin X, et al. Long Noncoding RNA VPS9D1-AS1 Sequesters microRNA-525-5p to Promote the Oncogenicity of Colorectal Cancer Cells by Upregulating HMGA1. Cancer Manag Res. 2020;12:9915–9928. https://doi.org/10.2147/CMAR.S273687. The image from Figure 3C, HOS, miR-490-3p mimic, has been duplicated with the image from Figure 5E, U-CH2, 2, from Li L, Lv G, Wang B, Ma H. RETRACTED ARTICLE: Long Noncoding RNA LINC00525 Promotes the Aggressive Phenotype of Chordoma Through Acting as a microRNA-505-3p Sponge and Consequently Raising HMGB1 Expression. Onco Targets Ther. 2020;13:9015–9027. https://doi.org/10.2147/OTT.S268678 (RETRACTED). When approached for an explanation, the authors have been unable to address the concerns raised and have not been able to provide sufficient original data from their study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The authors listed in this publication have been informed. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Abstract Background Undertreated risk factors are major contributors to the burden of cardiovascular disease (CVD). Those with arthritis have an increased prevalence of CVD risk factors. CVD risk factors are often asymptomatic, which may be a barrier their treatment. Arthritis causes pain and immobility, and is a common reason for individuals to seek healthcare. Our aims were to (1) examine the relationship between arthritis and CVD risk factors in Australian adults, and (2) calculate the proportion of CVD risk factors that could be reduced if individuals with arthritis were targeted. Methods This cross-sectional study uses data from the 2017–18 Australian National Health Survey which included 13,776 participants, categorised into young (18–39 years), middle aged (40–64 years) and older (≥ 65 years) adults. Hypertension, height and weight were measured. Arthritis, dyslipidemia and diabetes were self-reported. The associations between arthritis and CVD risk factors were examined using logistic regression, and the population attributable fraction (PAF) of arthritis for each CVD risk factor was calculated. Results Arthritis was reported by 4.0% of young adults, 28.8% of middle-aged adults and 54.5% of older adults. Those with arthritis were at increased odds of obesity (2.07 fold in young, 1.75 fold in middle-aged and 1.89 fold in older adults), increased odds of diabetes (5.70 fold in young, 1.64 fold in middle-aged and 1.37 fold in older adults), increased odds of hypertension (2.72 fold in young, 1.78 fold in middle-aged and 1.48 fold in older adults) and an increased odds of dyslipidaemia (4.64 fold in young, 2.14 fold in middle-aged and 1.22 fold in older adults) compared to those without arthritis. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. The PAF of the presence of arthritis for having at least one CVD risk factor was 30.7% in middle-aged adults and 70.4% in older adults. Conclusion Australian adults of all ages with arthritis are at increased odds of having CVD risk factors. For young and middle-aged adults, this increased odds remains significant even when adjusted for obesity. Presentation to healthcare practitioners with arthritis is an opportunity to screen for asymptomatic CVD risk factors with the potential of improving outcomes for both diseases. By adopting an approach of managing arthritis and CVD risk factors in parallel, rather than in silos, we could reduce the burden of CVD risk factors by 20–30%.

Shuo Wang,1 Biyu Lei,1 E Zhang,2 Puyang Gong,1 Jian Gu,1 Lili He,1 Lu Han,1 Zhixiang Yuan1 1College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China; 2Department of Basic Sciences, Officers College of People’s Armed Police, Chengdu, Sichuan, 610213, People’s Republic of ChinaCorrespondence: Zhixiang Yuan; Lu Han, Email zhixiang-yuan@hotmail.com; lunahan@swun.edu.cnAbstract: Inflammation is a beneficial and physiological process, but there are a number of inflammatory diseases which have detrimental effects on the body. In addition, the drugs used to treat inflammation have toxic side effects when used over a long period of time. Mesenchymal stem cells (MSCs) are pluripotent stem cells that can be isolated from a variety of tissues and can be differentiate into diverse cell types under appropriate conditions. They also exhibit noteworthy anti-inflammatory properties, providing new options for the treatment of inflammatory diseases. The therapeutic potential of MSCs is currently being investigated for various inflammatory diseases, such as kidney injury, lung injury, osteoarthritis (OA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). MSCs can perform multiple functions, including immunomodulation, homing, and differentiation, to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment under severe inflammatory conditions. In addition, accumulated evidence indicates that exosomes from extracellular vesicles of MSCs (MSC-Exos) play an extraordinary role, mainly by transferring their components to recipient cells. In this review, we summarize the mechanism and clinical trials of MSCs and MSC-Exos in various inflammatory diseases in detail, with a view to contributing to the treatment of MSCs and MSC-Exos in inflammatory diseases.Keywords: mesenchymal stem cells, exosome, inflammatory diseases, clinic data, drug delivery, targeted therapy

Yuan Yang,1,2 Ting Cui,1 Zuoxiao Li,2 Jinglun Li,2 Ting Duan,3 Zhengzhou Yuan,2 Changyi Wang,1 Jincheng Wan,1 Cao Li,4 Shujiang Zhang,2 Ling Li,2 Fayun Hu,1 Bo Wu1 1Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Radiology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Bo Wu; Fayun Hu, Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China, Tel +86-18980602142 ; +86-15902861270, Email dr.bowu@hotmail.com; hufayun2006@163.comObjective: This study examined the functional outcomes and safety of endovascular treatment (EVT) in acute ischemic stroke (AIS) patients owing to large vessel occlusion of the anterior circulation, presented during a late-time window (6– 24 hours after last seen well (LSW)) in a real-world practice.Methods: This was a retrospective analysis from a bi-center prospective cohort. According to the stroke treatment, patients with continuous Alberta Stroke Plan Early Aspect score (ASPECTS) ≥ 6 on non-contrast CT (NCCT) and moderate to good collateral state on CT angiography (CTA) were divided into EVT group and standard medical treatment (SMT) group. The primary outcome was the rate of functional independence (90-day mRS ≤ 2). Safety outcomes were the occurrence of symptomatic intracranial hemorrhage (sICH) and the 90-day mortality.Results: Among the 288 enrolled patients (53.5% male, median age 64 years), there were 167 patients in the EVT group and 121 in the SMT group. After multivariable adjustments for potential confounders, EVT was associated with functional independence (adjusted OR: 3.052; 95% confidence interval (CI): 1.553– 5.997; p = 0.001). In the PSM cohort, 44.2% (42/95) of patients in the EVT group versus 18.9% (18/95) in the SMT group achieved functional independence (OR: 3.39, 95% CI: 1.763– 6.517), and there was a significant difference favoring EVT over the SMT in the overall distribution of mRS (OR: 2.170, 95% CI: 1.302– 3.618) at 90 days. The rate of sICH did not differ between the EVT and SMT groups (10.5% vs 8.4%, p = 0.804) nor did 90-day mortality (18.9% vs 22.1%, p = 0.719). No interaction was found in p-values with statistical significance in subgroup analysis.Conclusion: This real-world experience suggests that EVT for late-presenting stroke patients, based on small core on NCCT and moderate to good collaterals on CTA, is associated with better outcomes than SMT alone, with no increase in sICH and 90-day mortality rates.Keywords: endovascular treatment, late time window, propensity score matching, real-world study

Liuting Zhou,1,2 Zhenyan Ye,3 E Zhang,4 Li Chen,1 Yitong Hou,1 JuChun Lin,2 Fenglan Huang,1 Zhixiang Yuan5 1Department of Osteoporosis, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, People’s Republic of China; 3School of Clinical Medical; Chengdu Medical College, Chengdu, People’s Republic of China; 4Officers college of PAP, Chengdu, Sichuan, People’s Republic of China; 5College of Pharmacy, Southwest Minzu University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Fenglan Huang, Email huangfenglan2011@sina.comPurpose: Mesangial cells-mediated glomerulonephritis refers to a category of immunologically mediated glomerular injuries characterized by infiltration of circulating inflammatory cells, proliferation of mesangial cells, and the common pathological manifestation to the later stage is renal fibrosis, accompanied by excessive accumulation of extracellular matrix (ECM). Treatment regimens include glucocorticoids and immunosuppressive agents, but their off-target distribution causes severe systemic toxicity. Hence, specific co-delivery of “anti-inflammatory/anti-fibrosis” drugs to the glomerular mesangial cell (MC) region is expected to produce better therapeutic effects.Methods: A novel kidney-targeted nanocarrier drug delivery system targeting MCs was constructed using passive targeting resulting from the difference in pore size between the glomerular endothelial layer and the basement membrane, and active targeting based on the specific binding of antibodies and antigens. Specifically, a liposome-nanoparticle hybrid (PLGA-LNHy) was formed by coating the surface of PLGA nanoparticles (NPs) with a phospholipid bilayer, and then PLGA-LNHy was co-modified with PEG and α 8 integrin antibodies to obtain PLGA immunoliposomes (PLGA-ILs).Results: The results showed that the obtained NPs had a core-shell structure, uniform and suitable particle size (119.1 ± 2.31 nm), low cytotoxicity, and good mesangial cell-entry ability, which can successfully accumulate in the glomerular MC region. Both dexamethasone (DXMS) and captopril (CAP) were loaded onto PLGA-ILs with a drug loading of 10.22 ± 1.00% for DXMS and 6.37 ± 0.25% for CAP (DXMS/CAP@PLGA-ILs). In vivo pharmacodynamics showed that DXMS/CAP@PLGA-ILs can effectively improve the pathological changes in the mesangial area and positive expression of proliferating cell nuclear antigen (PCNA) in glomeruli as well as reduce the expression of inflammatory factors, fibrotic factors and reactive oxygen species (ROS). Thus, renal inflammation and fibrosis were relieved.Conclusion: We have provided a strategy to increase nanoparticle accumulation in MCs with the potential to implement regulatory effects of anti-inflammatory and anti-fibrosis in glomerulonephritis (GN).Keywords: MCs, renal inflammatory, renal fibrosis, tem

Zhenzhen Yuan,&ast; Zhao Yang&ast; Orthopaedics, Tianjin Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhao Yang, Email anny.allan@126.comObjective: The aim of this study was to explore the naringin suppressive effect on human degenerative nucleus pulposus cells (D-NPCs) apoptosis and its mechanism.Methods: The degenerative NPCs were divided into 5 groups: the blank control (0μg/mL naringin), 10μg/mL, 20μg/mL, 40μg/mL and 100μg/mL naringin group. Flow cytometry and CCK-8 assay were used to determine the influence on the cell apoptosis and viability in the presence of naringin among groups. The expressions of genes and proteins related to apoptosis and ECM were detected, respectively. Finally, the inhibitors or agonist of apoptotic pathways were used for experiments.Results: In this study, we found naringin treatment led to a decrease of the D-NPCs apoptosis at an optimal concentration of 20μg/mL. After naringin treatment, the expressions of Wnt1 and β-catenin; Fas and Fasl; ATF-4 and CHOP; cleaved caspase-3 and caspase-8; P53 and P16INK4a; pro-apoptotic protein Bax were down‐regulated, while the expressions of anti-apoptotic protein Bcl-2, aggrecan and collagen II were up‐regulated in human D-NPCs. The inhibitors or agonist of pathways could promote or reverse the decrease of apoptosis of degenerative NPCs induced by naringin.Conclusion: Our data indicated that naringin had an antiapoptotic effect via inhibiting P53, P16INK4a, Wnt/β-catenin, and related apoptosis pathway, while the expression of ECM was increased in degenerative NPCs.Keywords: apoptosis, naringin, nucleus pulposus cells

Chenbo Xu,1 Lizhe Sun,1 Mengya Dong,2 Habib Ullah,3 Hameed Ullah,1 Juan Zhou,1,4 Zuyi Yuan1,5 1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, People’s Republic of China; 3Department of Cardiology, Dow University of Health and Sciences, Karachi, Pakistan; 4Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi’an, Shaanxi, People’s Republic of China; 5Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Zuyi Yuan; Hameed UllahDepartment of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of ChinaTel +86 29 8532 3819; +86 29 8532 3524Email zuyiyuan@mail.xjtu.edu.cn; 807287144@qq.comPurpose: Anion gap (AG) is a valuable and easily obtained clinical tool for differentially diagnosis of acid-base disorders. Current understanding of the prognostic impact of AG on mortality after acute myocardial infarction (AMI) is limited. We aimed to investigate whether AG is a predictor of short-term and long-term all-cause mortality after AMI.Patients and Methods: We examined 1806 patients diagnosed with AMI in intensive care unit from the Medical Information Mart for Intensive Care III (MIMIC-III) database. We analyzed the association of AG with 30-day, 180-day and 1-year all-cause mortality on a continuous scale and in categories, using multivariable Cox regression. We utilized restricted cubic splines to evaluate the linearity between hazard ratio (HR) and AG concentrations.Results: AG was associated with a higher risk of 30-day, 180-day and 1-year all-cause mortality, with adjusted HRs of 1.083 (95% CI 1.051 to 1.117), 1.077 (95% CI 1.049 to 1.105), and 1.074 (95% CI 1.047 to 1.101), respectively. The results were consistent in subgroup analyses. The association between AG and all-cause mortality was linear for 180-day and 1-year mortality, and near linear for 30-day mortality, as higher concentrations were associated with high all-cause mortality. When stratified according to quartiles, AG was associated with 30-day mortality (HR[95% CI]: second quartile, 2.243[1.273, 3.955]; third quartile, 3.026[1.763, 5.194]; top quartile, 4.402[2.573, 7.531]), 180-day mortality (HR[95% CI]: second quartile, 1.719[1.118, 2.645]; third quartile, 2.362[1.575, 3.542]; top quartile, 3.116[2.077, 4.676]), and 1-year mortality (HR[95% CI]: second quartile, 1.700[1.143, 2.528]; third quartile, 2.239[1.536, 3.264]; top quartile, 2.876[1.969, 4.201]) using bottom quartile as reference.Conclusion: We firstly demonstrated that higher AG was significantly associated with increased 30-day, 180-day and 1-year all-cause mortality in AMI patients. AG as an easily obtained marker is of strong and reliable predictive value for AMI mortality during follow-up.Keywords: acute myocardial infarction, anion gap, all-cause mortality

Xin Hua,1,&ast; Fangfang Duan,1,&ast; Wenyu Zhai,2,&ast; Chenge Song,1 Chang Jiang,1 Li Wang,1 Jiajia Huang,1 Huanxin Lin,3 Zhongyu Yuan1 1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Department of Radiotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhongyu YuanDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China, Email yuanzhy@sysucc.org.cnHuanxin LinDepartment of Radiotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China, Email linhx@sysucc.org.cnPurpose: We attempted to explore the prognostic value of baseline inflammatory and nutritional biomarkers at diagnosis in patients with early-stage breast cancer and develop a novel scoring system, the inflammatory-nutritional prognostic score (INPS).Patients and Methods: We collected clinicopathological and baseline laboratory data of 1259 patients with early-stage breast cancer between December 2010 and November 2012 from Sun Yat-sen University Cancer Center. Eligible patients were randomly divided into training and validation cohorts (n = 883 and 376, respectively) in a 7:3 ratio. We selected the most valuable biomarkers to develop INPS by the least absolute shrinkage and selection operator (LASSO) Cox regression model. A prognostic nomogram incorporating INPS and other independent clinicopathological factors was developed based on the stepwise multivariate Cox regression method. Then, we used the concordance index (C-index), calibration plot, and time-dependent receiver operating characteristic (ROC) analysis to evaluate the prognostic performance and predictive accuracy of the predictive nomogram.Results: Four inflammatory-nutritional biomarkers, including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), prognostic nutritional index (PNI), and albumin-alkaline phosphatase ratio (AAPR), were selected using the LASSO Cox analysis to construct INPS, which remained an independent prognostic indicator per the multivariate Cox regression analysis. Patients were stratified into low- and high-INPS groups based on the cutoff INPS determined by the maximally selected rank statistics. The prognostic model for overall survival consisting of INPS and other independent clinicopathological indicators showed excellent discrimination with C-indexes of 0.825 (95% confidence interval [CI]: 0.786– 0.864) and 0.740 (95% CI: 0.657– 0.822) in the training and validation cohorts, respectively. The time-dependent ROC curves showed a higher predictive accuracy of our prognostic nomogram than that of traditional tumor-node-metastasis staging.Conclusion: Baseline INPS is an independent indicator of OS in patients with early-stage breast cancer. The INPS-based prognostic nomogram could be used as a practical tool for individualized prognostic predictions.Keywords: early-stage breast cancer, LASSO Cox analysis, inflammatory-nutritional biomarker, prognostic nomograms, overall survival

Abstract Background Hand osteoarthritis is a common and disabling chronic joint disease with a lack of effective therapies. Emerging evidence suggests the role of local inflammation in causing pain in hand osteoarthritis. Corticosteroids are potent anti-inflammatory drugs used in many rheumatic diseases. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether topical corticosteroid reduces pain over 6 weeks in patients with hand osteoarthritis. Methods One hundred participants with hand osteoarthritis will be recruited from the community in Melbourne, Australia, and randomly allocated in a 1:1 ratio to receive either topical Diprosone OV or placebo ointment administered 3 times daily on the painful hand joints for 6 weeks. The primary outcome is pain reduction (assessed by 100 mm visual analogue scale) at 6 weeks. The secondary outcomes include changes in pain and function assessed using Functional Index for Hand Osteoarthritis, Australian Canadian Osteoarthritis Hand Index, Michigan Hand Outcomes Questionnaire, and tender and swollen joint count at 6 weeks. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups. Discussion This study will provide high-quality evidence to determine whether topical corticosteroid reduces pain over 6 weeks in patients with hand osteoarthritis, with major clinical and public health importance by informing clinical practice guidelines for the management of hand osteoarthritis and reducing the burden of the disabling disease. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12620000599976 . Registered 22 May 2020.

Shuanghong Luo,1,2 Chuncheng Wu,3 Qiuhong Luo,1,2 Mengdong Ran,4 Yin Liu,5 Fei Lei,6 Xin Chen,7 Zheng Yuan,8 Hanmin Liu,1,2 Chaomin Wan1,2 1Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of China; 3Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Biostatistics, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 5Research and Development Department, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 6Medical Information Center, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 7Child Health Care Department, Nanxin Community Health Service Center, High-Tech Zone, Chengdu, People’s Republic of China; 8Economics School, Southwestern University of Finance and Economics, Chengdu, People’s Republic of ChinaCorrespondence: Chaomin Wan Tel/Fax +86-28-85503185Email wanchaomin@scu.edu.cnAbstract: As an implementation strategy, the actual functional scope of clinical pathway (CPW) can be mastered is the basis for evaluating and improving CPW management, which is very important for bridging the evidence-to-practice gap. Here, we propose and discuss a design and evaluation model for CPWs through some theoretical lenses that may help the designer master the actual functional scope of CPWs and accumulate and refine effective key management steps of a specific disease. We can thus determine the best-optimized design with the largest net benefit that allows definition of the core management steps for a specific disease.Keywords: implementation science, clinical pathway, evidence-based medicine, health technology assessment, public health economics

Abstract Skeletal muscle plays an important role in glycaemic control and metabolic homeostasis, making it a tissue of interest with respect to type 2 diabetes mellitus. The aim of the present study was to determine if ligands of Toll-like receptors (TLRs) could have an impact on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. The myotubes expressed mRNA for TLRs 1–6. TLR3, TLR4, TLR5 and TLR6 ligands (TLRLs) increased glucose metabolism. Furthermore, TLR4L and TLR5L increased oleic acid metabolism. The metabolic effects of TLRLs were not evident until after at least 24 h pre-incubation of the cells and here the metabolic effects were more evident for the metabolism of glucose than oleic acid, with a shift towards effects on oleic acid metabolism after chronic exposure (168 h). However, the stimulatory effect of TLRLs on myokine expression and secretion was detected after only 6 h, where TLR3-6L stimulated secretion of interleukin-6 (IL-6). TLR5L also increased secretion of interleukin-8 (IL-8), while TLR6L also increased secretion of granulocyte–macrophage colony stimulating factor (GM-CSF). Pre-incubation of the myotubes with IL-6 for 24 h increased oleic acid oxidation but had no effect on glucose metabolism. Thus IL-6 did not mimic all the metabolic effects of the TLRLs, implying metabolic effects beyond the actions of this myokine.

Jing Yuan,1,&ast; Fangfang Duan,2,&ast; Wenyu Zhai,3,&ast; Chenge Song,2 Li Wang,2 Wen Xia,2 Xin Hua,2 Zhongyu Yuan,2 Xiwen Bi,2 Jiajia Huang2 1Departments of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Departments of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Departments of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiajia Huang; Xiwen BiDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaEmail huangjiaj@sysucc.org.cn; bixw@sysucc.org.cnBackground: Aging, an inevitable process characterized by functional decline over time, is a significant risk factor for various tumors. However, little is known about aging-related genes (ARGs) in breast cancer (BC). We aimed to explore the potential prognostic role of ARGs and to develop an ARG-based prognosis signature for BC.Methods: RNA-sequencing expression profiles and corresponding clinicopathological data of female patients with BC were obtained from public databases in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). An ARG-based risk signature was constructed in the TCGA cohort based on results of least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, and its prognostic value was further validated in the GSE20685 cohort.Results: A six ARG-based signature, including CLU, DGAT1, MXI1, NFKBI, PIK3CA and PLAU, was developed in the TCGA cohort and significantly stratified patients into low- and high-risk groups. Patients in the former group showed significantly better prognosis than those in the latter. Multivariate Cox regression analysis demonstrated that the ARG risk score was an independent prognostic factor for BC. A predictive nomogram integrating the ARG risk score and three identified factors (age, N- and M-classification) was established in the TCGA cohort and validated in the GSE20685 cohort. Calibration plots showed good consistency between predicted survival probabilities and actual observations.Conclusion: A novel ARG-based risk signature was developed for patients with BC, which can be used for individual prognosis prediction and promoting personalized treatment.Keywords: breast cancer, aging, prognostic signature, risk stratification

Objective: While targeting obesity is central to osteoarthritis management, recent meta-analyses demonstrate only modest effects of weight loss on symptoms, and little on structure. The World Health Organisation recommends that effective management of obesity include prevention of weight gain, weight maintenance and weight loss. Therefore, we systematically reviewed the recommendations and approaches for management of obesity in clinical practice guidelines (CPGs) for osteoarthritis. Design: Nine databases were searched (01.01.2010–15.03.2022) to identify guidelines informing the non-pharmacological management of osteoarthritis. Three reviewers appraised guidelines according to the AGREE II instrument, and independently extracted data on their characteristics. One author extracted and summarised guideline recommendations on weight management. This systematic review is registered on PROSPERO (CRD42021274195). Results: Of the included fifteen CPGs (median AGREE II domain score 78.7%), weight loss was recommended for knee (12 of 13) and hip (10 of 11) but not hand (0 of 4) osteoarthritis. Combination approaches of diet and/or exercise were recommended for overweight or obese individuals in knee (8 of 12) and hip (4 of 10) osteoarthritis. Two guidelines specified ≥5% weight loss. One guideline specified strategies for maintenance of lost weight; none specifically recommended preventing weight gain. There was discordance between strength of recommendation for weight loss and level of evidence (3 of 15). Conclusion: Most CPGs for knee and hip osteoarthritis recommend weight loss to manage obesity in osteoarthritis. As steady weight accumulation is common in adults, preventing weight gain should also be considered as it is a missed opportunity to improve outcomes in osteoarthritis.

Fangfang Duan,&ast; Chenge Song,&ast; Yuyu Ma, Kuikui Jiang, Fei Xu, Xiwen Bi, Jiajia Huang, Ruoxi Hong, Zhangzan Huang, Qianyi Lu, Zhongyu Yuan, Shusen Wang, Wen Xia Departments of Medical Oncology, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen XiaDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaEmail xiawen@sysucc.org.cnBackground: There are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population.Methods: The clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities.Results: A total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710– 0.767) for the PFS nomogram and 0.752 (95% CI: 0.717– 0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities.Conclusion: We constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.Keywords: prognostic nomogram, metastatic breast cancer, everolimus, progression-free survival, overall survival

Xiaoyan Huang,1– 3,* Yingyi Kuang,1– 3,* Qiyuan Qin,1– 3,* Miaomiao Zhu,1– 3 Yanjiong He,1– 3 Zixu Yuan,1– 3 Huaiming Wang,1– 3 Qinghua Zhong,1,2,4 Qi Guan,1– 3 Hui Wang,1– 3,* Tenghui Ma,1– 3,* Xinjuan Fan1,2,5,* 1Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 3Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 4Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 5Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinjuan FanDepartment of Pathology, Sun Yat-sen University Sixth Affiliated Hospital, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, People’s Republic of ChinaFax +86 20-38737621Email fanxjuan@mail.sysu.edu.cnTenghui MaDepartment of Colorectal Surgery, Sun Yat-sen University Sixth Affiliated Hospital, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, People’s Republic of ChinaFax +86 20-38737621Email matengh@mail.sysu.edu.cnBackground: Chronic radiation intestinal injury (CRII) is the most common complication after pelvic malignancy radiation. Once hemorrhagic CRII patients suffer from lower extremity deep venous thrombosis (LE-DVT), hemostasis and anticoagulation therapy will be adopted simultaneously, but the treatment strategy is a paradox, as the condition is extremely intractable and serious. The aim of this study was to investigate the prevalence of and risk factors for LE-DVT in CRII patients and explore the treatment of hemorrhagic CRII patients with LE-DVT.Methods: This was a retrospective study, and a total of 608 hospitalized CRII patients after pelvic radiotherapy were included from November 2011 to October 2018. Univariate and multivariate analyses were conducted to investigate the potential risk factors for LE-DVT in CRII patients. Furthermore, the treatment of hemorrhagic CRII patients with LE-DVT was explored.Results: Among the CRII patients, 94 (15.5%) were with suspicious symptoms of LE-DVT in the lower limbs, and 32 (5.3%) were diagnosed with LE-DVT. Among the patients with LE-DVT, 65.6% (21/32) had bleeding simultaneously, and 29 (90.6%) had anemia with 24 (75.0%) having moderate to severe anemia. Multivariate analysis showed that a recent surgical history (≤ 6 months) (OR = 5.761, 95% CI: 2.506∼ 13.246, p < 0.001), tumor recurrence or metastasis (OR = 3.049, 95% CI: 1.398∼ 6.648, p = 0.005) and the hemoglobin (Hb) level (OR = 0.960, 95% CI: 0.942∼ 0.979, p < 0.001) were significantly associated with the development of LE-DVT. ROC curve analysis showed that the AUC of the merged risk score of the independent risk factors was 0.822 (95% CI: 0.789∼ 0.852), and the optimal Hb cutoff was 82.5 g/L. After colostomy, obvious bleeding remission was rapidly found in 84.6% of hemorrhagic CRII patients with LE-DVT.Conclusion: The prevalence of LE-DVT in hospitalized CRII patients was 5.3%. A recent surgical history, tumor recurrence or metastasis and a lower Hb level were independently associated with LE-DVT development in CRII patients. Colostomy could be a good choice for intractable hemorrhagic CRII patients with LE-DVT.Keywords: chronic radiation intestinal injury, lower extremity deep venous thrombosis, pelvic malignancy radiation, risk factor, colostomy, hemorrhagic